DE4229050A1 - New esters and amides of 9-chloro-prostaglandins - useful, e.g., in treatment of glaucoma and as diuretic agents - Google Patents
New esters and amides of 9-chloro-prostaglandins - useful, e.g., in treatment of glaucoma and as diuretic agentsInfo
- Publication number
- DE4229050A1 DE4229050A1 DE4229050A DE4229050A DE4229050A1 DE 4229050 A1 DE4229050 A1 DE 4229050A1 DE 4229050 A DE4229050 A DE 4229050A DE 4229050 A DE4229050 A DE 4229050A DE 4229050 A1 DE4229050 A1 DE 4229050A1
- Authority
- DE
- Germany
- Prior art keywords
- chloro
- general formula
- dihydroxy
- pentanor
- cyclohexyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 150000001408 amides Chemical class 0.000 title claims abstract description 12
- 229940094443 oxytocics prostaglandins Drugs 0.000 title abstract description 7
- 239000002934 diuretic Substances 0.000 title abstract description 5
- 150000002148 esters Chemical class 0.000 title abstract description 4
- 208000010412 Glaucoma Diseases 0.000 title description 4
- 238000000034 method Methods 0.000 claims abstract description 7
- -1 phenacyl ester Chemical class 0.000 claims abstract description 7
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 5
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 claims abstract description 5
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 20
- 239000000460 chlorine Substances 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 239000002798 polar solvent Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 125000005907 alkyl ester group Chemical group 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 abstract description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 abstract description 7
- 125000000217 alkyl group Chemical group 0.000 abstract description 7
- 230000004087 circulation Effects 0.000 abstract description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 abstract description 6
- 150000003180 prostaglandins Chemical class 0.000 abstract description 6
- 125000001424 substituent group Chemical group 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 4
- 125000005843 halogen group Chemical group 0.000 abstract description 4
- 241000700159 Rattus Species 0.000 abstract description 3
- 239000006210 lotion Substances 0.000 abstract description 3
- 239000002674 ointment Substances 0.000 abstract description 3
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 abstract description 2
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 abstract description 2
- 230000001737 promoting effect Effects 0.000 abstract description 2
- 230000004406 elevated intraocular pressure Effects 0.000 abstract 1
- 239000011505 plaster Substances 0.000 abstract 1
- 238000010626 work up procedure Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 230000004410 intraocular pressure Effects 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 229940086542 triethylamine Drugs 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000001882 diuretic effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- PPNCOQHHSGMKGI-UHFFFAOYSA-N 1-cyclononyldiazonane Chemical compound C1CCCCCCCC1N1NCCCCCCC1 PPNCOQHHSGMKGI-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- WADSJYLPJPTMLN-UHFFFAOYSA-N 3-(cycloundecen-1-yl)-1,2-diazacycloundec-2-ene Chemical compound C1CCCCCCCCC=C1C1=NNCCCCCCCC1 WADSJYLPJPTMLN-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 108010069102 Thromboxane-A synthase Proteins 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- GPEHQHXBPDGGDP-UHFFFAOYSA-N acetonitrile;propan-2-one Chemical compound CC#N.CC(C)=O GPEHQHXBPDGGDP-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 229940006138 antiglaucoma drug and miotics prostaglandin analogues Drugs 0.000 description 1
- 239000003418 antiprogestin Substances 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000003480 fibrinolytic effect Effects 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000003199 leukotriene receptor blocking agent Substances 0.000 description 1
- 230000029860 luteolysis Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 150000003163 prostaglandin D2 derivatives Chemical class 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000008327 renal blood flow Effects 0.000 description 1
- 230000008326 skin blood flow Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
- C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
- C07C405/0041—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing nitrogen
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Nanotechnology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Biotechnology (AREA)
- Medical Informatics (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- General Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Gegenstand der vorliegenden Erfindung sind Ester und Amide von 9-Chlor-Prostaglan dinanaloga, Verfahren zu ihrer Herstellung sowie ihre Verwendung als Arzneimittel.The present invention relates to esters and amides of 9-chloro-prostaglan dinanalogues, processes for their preparation and their use as medicines.
Aus dem umfangreichen Stand der Technik der Prostaglandine und ihrer Analoga weiß man, daß diese Stoffklasse aufgrund ihrer biologischen und pharmakologischen Eigen schaften zur Behandlung von Säugetieren, einschließlich des Menschen, geeignet ist. Ihre Verwendung als Arzneimittel stößt jedoch auf Schwierigkeiten. Die meisten natürlichen Prostaglandine besitzen eine für therapeutische Zwecke zu kurze Wirkdauer, da sie zu rasch durch verschiedene enzymatische Prozesse abgebaut werden. Alle Strukturverände rungen haben daher das Ziel, sowohl die Wirkdauer als auch die Selektivität der Wirkung zu steigern.Knows from the extensive state of the art of prostaglandins and their analogues one that this class of substances due to their biological and pharmacological properties is suitable for the treatment of mammals, including humans. Your However, use as a drug is difficult. Most natural Prostaglandins have a short duration of action for therapeutic purposes because they are too can be rapidly broken down by various enzymatic processes. All structural changes Therefore, the aim is to achieve both the duration and the selectivity of the effect to increase.
Es wurde nun gefunden, daß die neuen 9-Chlor-Prostaglandinester und -amide eine hohe Wirkspezifität, bessere Wirksamkeit, längere Wirkdauer und vor allen Dingen höhere Stabilität als die natürlichen Prostaglandine besitzen.It has now been found that the new 9-chloro prostaglandin esters and amides have a high Effect specificity, better effectiveness, longer duration of action and above all higher Have stability than the natural prostaglandins.
Die Erfindung betrifft 9-Chlor-Prostaglandinester und -amide der allgemeinen Formel (I)The invention relates to 9-chloro prostaglandin esters and amides of the general formula (I)
worin
X Sauerstoff oder CH2,
R1 COOR2,
wobei R2 einen gegebenenfalls substituierten Phenacyl-Rest darstellt,
oder CONHR3
mit R3 in der Bedeutung eines gegebenenfalls substituierten C1-C10-Alkyl-
Restes,
bedeuten.wherein
X is oxygen or CH 2 ,
R 1 COOR 2 ,
where R 2 represents an optionally substituted phenacyl radical,
or CONHR 3
with R 3 as an optionally substituted C 1 -C 10 alkyl radical,
mean.
Als Substituenten für den Phenacylrest R2 kommen geradkettige oder verzweigte C1-C4- Alkyl-Reste wie Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl und tert. Butyl sowie die Halogenatome Chlor, Brom und Iod in Betracht.The substituents for the phenacyl radical R 2 are straight-chain or branched C 1 -C 4 -alkyl radicals such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert. Butyl and the halogen atoms chlorine, bromine and iodine into consideration.
Als Alkylgruppen R3 sind geradkettige oder verzweigte Alkylgruppen mit 1-10 C-Atomen zu betrachten, wie beispielsweise Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.- Butyl, Pentyl, Isopentyl, Neopentyl, Hexyl, Heptyl. Die Alkylgruppen R3 können gegebe nenfalls ein- bis mehrfach substituiert sein durch Halogenatome, Hydroxygruppen, Alk oxygruppen, oder gegebenenfalls substituierte Arylgruppen. Als Substituenten seien bei spielsweise genannt Fluor, Chlor oder Brom, Hydroxy, Methoxy, Ethoxy, Phenyl. Als be vorzugte Alkylgruppen R3 sind solche mit 1-5 C-Atomen, wie z. B. Methyl, Ethyl, Propyl, Isopropyl, Isobutyl, Butyl, und als bevorzugte Substituenten Fluor, Hydroxy und Methoxy zu nennen.As alkyl groups R 3 straight-chain or branched alkyl groups with 1-10 C atoms are to be considered, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl. The alkyl groups R 3 can optionally be mono- to polysubstituted by halogen atoms, hydroxyl groups, alkoxy groups, or optionally substituted aryl groups. Examples of substituents are fluorine, chlorine or bromine, hydroxy, methoxy, ethoxy, phenyl. As preferred alkyl groups R 3 are those with 1-5 carbon atoms, such as. As methyl, ethyl, propyl, isopropyl, isobutyl, butyl, and fluorine, hydroxy and methoxy as preferred substituents.
Für die Arylgruppen als Substituenten der Alkylreste R3 kommen sowohl substituierte wie auch unsubstituierte Arylgruppen in Betracht, wie beispielsweise Phenyl, 1-Naphtyl und 2- Naphthyl, die jeweils substituiert sein können durch 1-3 Halogenatome, eine Phenylgrup pe, 1-3 Alkylgruppen mit jeweils 1-4 C-Atomen, eine Chlormethyl, Fluormethyl-, Trifluormethyl-, Carboxyl-, Hydroxy- oder Alkoxygruppe mit 1-4 C-Atomen. Bevorzugt sind die Substituenten in 3- und 4-Stellung am Phenylring, zum Beispiel durch Fluor, Chlor, Alkoxy oder Trifluormethyl oder in 4-Stellung durch Hydroxy.For the aryl groups as substituents of the alkyl radicals R 3 , both substituted and unsubstituted aryl groups are suitable, such as, for example, phenyl, 1-naphthyl and 2-naphthyl, which can each be substituted by 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups each with 1-4 C atoms, a chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, hydroxyl or alkoxy group with 1-4 C atoms. The substituents in the 3- and 4-position on the phenyl ring are preferred, for example by fluorine, chlorine, alkoxy or trifluoromethyl or in the 4-position by hydroxy.
Die Erfindung betrifft ferner ein Verfahren zur Herstellung der 9-Chlor-Prostaglandinester und -amide der Formel I, dadurch gekennzeichnet, daß manThe invention further relates to a method for producing the 9-chloro-prostaglandin esters and amides of the formula I, characterized in that
-
a) eine Verbindung der Formel II
worin
X die oben angegebene Bedeutung aufweist,
unter Zusatz einer geeigneten Base mit einem gegebenenfalls substituierten Halogenaceto phenonderivat der allgemeinen Formel III worin
R4 C1-C4-Alkyl-, Chlor, Brom, oder Iod und
Hal Chlor oder Brom bedeuten,
in einem polaren Lösungsmittel zu Verbindungen der allgemeinen Formel (Ia) umsetzt, oder a) a compound of formula II wherein
X has the meaning given above,
with the addition of a suitable base with an optionally substituted haloaceto phenone derivative of the general formula III wherein
R 4 is C 1 -C 4 alkyl, chlorine, bromine, or iodine and
Hal means chlorine or bromine,
in a polar solvent to give compounds of the general formula (Ia), or -
b) einen Alkylester der allgemeinen Formel Ib
worin
X die oben angegebene Bedeutung aufweist,
ohne Lösungsmittel mit einem Amin der allgemeinen Formel IVH2N-R3 (IV)zu Verbindungen der allgemeinen Formel Ic umsetzt.b) an alkyl ester of the general formula Ib wherein
X has the meaning given above,
without solvent with an amine of the general formula IVH 2 NR 3 (IV) to give compounds of the general formula Ic implements.
Als Base für die Umsetzung von Verbindungen der allgemeinen Formel II mit Verbindun gen der allgemeinen Formel III sind die dem Fachmann bekannten Basen, z. B. Triethyl amin, Diisopropylethylamin, Diazabicycloundecen, Diazabicyclononan, N,N-Dimethyl aminopyridin, Kaliumcarbonat oder Cäsiumcarbonat besonders geeignet. As a base for the reaction of compounds of general formula II with compounds gene of general formula III are the bases known to those skilled in the art, e.g. B. Triethyl amine, diisopropylethylamine, diazabicycloundecene, diazabicyclononane, N, N-dimethyl aminopyridine, potassium carbonate or cesium carbonate are particularly suitable.
Die Umsetzung kann in allen polaren Lösungsmitteln, z. B. Aceton Acetonitril, Dimethyl formamid, oder Dimethylsulfoxid erfolgen.The reaction can be carried out in all polar solvents, e.g. B. acetone acetonitrile, dimethyl formamide, or dimethyl sulfoxide.
Die Synthese der Phenacylester (5Z,13E)-(9R,11R,15S)-9-Chlor-15-cyclohexyl-11,15-di hydroxy-16,17,18,19,20-pentanor-5,13-prostadiensäurephenacylester und (5Z,13E)- (9R,11R,15S)-9-Chlor-3-oxa-15-cyclohexyl-11,15-dihydroxy-16,17,18,19-,20-pentanor- 5,13-prostadiensäurephenacylester in den Beispielen 1 und 3 ist allgemein anwendbar als Verfahren zur Herstellung von Phenacylestern von 9-Chlor-Prostaglandinderivaten.The synthesis of the phenacyl esters (5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-di hydroxy-16,17,18,19,20-pentanor-5,13-prostadienoic acid phenacyl ester and (5Z, 13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11,15-dihydroxy-16,17,18,19-, 20-pentanor- 5,13-prostadienoic acid phenacylester in Examples 1 and 3 is generally applicable as Process for the preparation of phenacyl esters of 9-chloro-prostaglandin derivatives.
Die Synthese der Amide (5Z,13E)-(9R,11R,15S)-9-Chlor-15-cyclohexyl-11,15-dihydroxy- 16,17,18,19,20-pentanor-5,13-prostadiensäure-(3-hydroxypropyl)-amid und (5Z,13E)- (9R,11R,15S)-9-Chlor-3-oxa-15-cyclohexyl-11,15-dihydroxy-16,17,18,19-,20-pentanor- 5,13-prostadiensäure-(3-hydroxypropyl)-amid in den Beispielen 2 und 4 ist allgemein anwendbar als Verfahren zur Herstellung der Amide von 9-Chlor-Prostaglandinderivaten.The synthesis of the amides (5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-dihydroxy- 16,17,18,19,20-pentanor-5,13-prostadienoic acid- (3-hydroxypropyl) -amide and (5Z, 13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11,15-dihydroxy-16,17,18,19-, 20-pentanor- 5,13-prostadienoic acid (3-hydroxypropyl) amide in Examples 2 and 4 is general applicable as a process for the preparation of the amides of 9-chloro-prostaglandin derivatives.
Die für die Synthese der Ester und Amide benötigten Ausgangsmaterialien sind nach Vor schriften aus EP 299 914 und WO 86/05488 zu erhalten.The starting materials required for the synthesis of the esters and amides are as above to obtain documents from EP 299 914 and WO 86/05488.
Die Erfindung betrifft auch Arzneimittel auf Basis der Verbindungen der Formel I, sowie deren Cyclodextrinclathrate, mit den üblichen Hilfs- und Trägerstoffen.The invention also relates to medicaments based on the compounds of the formula I, and their cyclodextrin clathrates, with the usual auxiliaries and carriers.
Cyclodextrinclathrate können analog einer Vorschrift in WO 87/05294 erhalten werden.Cyclodextrin clathrates can be obtained analogously to a regulation in WO 87/05294.
Die erfindungsgemäßen 9-Chlor-Prostaglandinester und -amide sind stabile PGD2-Derivate und damit wertvolle Pharmaka, da sie bei ähnlichem Wirkungsspektrum eine wesentlich verbesserte (höhere Spezifität) und vor allem wesentlich längere Wirkung aufweisen als die entsprechenden natürlichen Prostaglandine.The 9-chloro prostaglandin esters and amides according to the invention are stable PGD 2 derivatives and thus valuable pharmaceuticals, since they have a significantly improved (higher specificity) and, above all, significantly longer activity than the corresponding natural prostaglandins with a similar spectrum of activity.
Sie sind als medizinisch wertvolle Wirkstoffe zur Anwendung für z. B. Blutdrucksenkung, die Förderung der Hautdurchblutung, Luteolyse, Hemmung der Magensäuresekretion, Plättchenaggregationshemmung, Ulkusheilung oder Zytoprotektion geeignet. They are medicinally valuable active ingredients for use for. B. lowering blood pressure, the promotion of skin circulation, luteolysis, inhibition of gastric acid secretion, Inhibits platelet aggregation, ulcer healing or cytoprotection.
Die erfindungsgemäßen Verbindungen können auch in Kombination, z. B. mit β-Blockern, Diuretika, Phosphodiesterasehemmern, Calciumantagonisten, Thromboxanantagonisten, Thromboxansynthetase- und Cyclooxygenasehemmern, gerinnungshemmenden Substan zen, wie auch Fibrinolytika, Leukotrienantagonisten, Leukotriensynthetasehemmern und Antigestagenen, verwendet werden.The compounds of the invention can also in combination, for. B. with β-blockers, Diuretics, phosphodiesterase inhibitors, calcium antagonists, thromboxane antagonists, Thromboxane synthetase and cyclooxygenase inhibitors, anticoagulant substances zen, as well as fibrinolytics, leukotriene antagonists, leukotriene synthetase inhibitors and Antigestagens can be used.
Besonders geeignet sind die erfindungsgemäßen Verbindungen zur lokalen Anwendung wie z. B. zur Förderung der Hautdurchblutung und zur Senkung erhöhten Augeninnendruckes (Glaukom), sowie zur Förderung der Nierendurchblutung und zur Verwendung als Diuretikum.The compounds according to the invention are particularly suitable for local use such as B. increased to promote skin circulation and lowering Intraocular pressure (glaucoma), as well as to promote renal blood flow and Use as a diuretic.
Bei Kaninchen bewirkt die lokale Applikation der Verbindungen eine Senkung des Au geninnendruckes.In rabbits, the local application of the compounds causes a reduction in the Au internal pressure.
Bei Affen mit experimentellem Glaukom bewirkt die lokale Applikation der Verbindungen eine Normalisierung des pathologisch erhöhten Augeninnendruckes.In monkeys with experimental glaucoma, the local application of the compounds causes a normalization of the pathologically increased intraocular pressure.
Die Einzeldosis der Verbindungen für die Anwendung zur Behandlung erhöhten Augenin nendruckes ist 1 ng-100 µg / Auge, einmal oder mehrmals täglich, wenn sie am mensch lichen Patienten lokal verabreicht werden.The single dose of the compounds for use in the treatment increased eye The pressure is 1 ng-100 µg / eye, once or several times a day when it is in humans patients are administered locally.
Für die lokale Applikation für die Anwendung zur Behandlung erhöhten Augeninnen druckes sind beispielsweise Lösungen, Lotionen oder Salben geeignet.For local application for use in the treatment of raised inner eyes For example, solutions, lotions or ointments are suitable.
Die Dosis der Verbindungen bei lokaler Anwendung zur Förderung der Hautdurchblutung ist 5-500 ng/cm2, wenn sie am menschlichen Patienten verabreicht werden.The dose of the compounds when used topically to promote skin circulation is 5-500 ng / cm 2 when administered to human patients.
Für die lokale Applikation für die Anwendung zur Förderung der Hautdurchblutung sind beispielsweise Lösungen, Lotionen, Salben, Cremes oder Pflaster geeignet.For local application for use to promote skin circulation for example, solutions, lotions, ointments, creams or plasters.
Die erfindungsgemäßen Wirkstoffe sollen in Verbindung mit den in der Galenik bekannten und üblichen Hilfsstoffen, z. B. zur Herstellung von Präparaten zur Förderung der Haut durchblutung, zur Behandlung des erhöhten Augeninnendruckes (Glaukom), zur Förde rung der Nierendurchblutung oder zur Verwendung als Diuretikum dienen. The active compounds according to the invention are intended to be used in conjunction with those known in galenics and usual auxiliaries, e.g. B. for the preparation of preparations for promoting the skin blood circulation, to treat increased intraocular pressure (glaucoma), to promote tion of the kidney or for use as a diuretic.
Die folgenden Beispiele sollen die Erfindung näher erläutern, ohne daß damit eine Begren zung vorgenommen werden soll.The following examples are intended to explain the invention in more detail without restricting it should be made.
Zu einer Lösung aus 100 mg (5Z,13E)-(9R,11R,15S)-9-Chlor-15-cyclohexyl-11,15-dihy
droxy-16,17,18,19,20-pentanor-5,13-prostadiensäure und 75 mg w-Bromacetophenon in
2.6 ml Acetonitril gibt man 0.057 ml Triethylamin in 1.25 ml Aceton und rührt anschlie
ßend 18 Stunden bei 24°C unter Argon. Man gibt dann nochmal 40 mg w-Bromacetophe
non zu und rührt nochmals 16 Stunden bei 24°C unter Argon. Dann verdünnt man mit 80
ml Essigester, wäscht einmal mit 10 ml einer Mischung aus gesättigter Natriumchlorid-Lö
sung und Wasser (1 : 1), trocknet über Natriumsulfat und engt im Vakuum ein. Das Roh
produkt reinigt man durch Säulenchromatographie an Kieselgel. Mit Hexan / 0 - 80% Es
sigester als Elutionsmittel erhält man 114 mg der Titelverbindung als farbloses Öl.
IR (CHCl3): 3607, 3400 (br.), 3065, 3030, 3003, 2928, 2857, 1742, 1705, 1600, 1450,
1376, 1155, 1084, 1002, 972 cm-1.To a solution of 100 mg (5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor-5,13 -prostadienic acid and 75 mg w-bromoacetophenone in 2.6 ml acetonitrile, 0.057 ml triethylamine in 1.25 ml acetone are added and the mixture is then stirred at 24 ° C. under argon for 18 hours. Another 40 mg of w-bromoacetophe non are then added and the mixture is stirred for a further 16 hours at 24 ° C. under argon. Then diluted with 80 ml of ethyl acetate, washed once with 10 ml of a mixture of saturated sodium chloride solution and water (1: 1), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by column chromatography on silica gel. With hexane / 0 - 80% ethyl acetate as the eluent, 114 mg of the title compound are obtained as a colorless oil.
IR (CHCl 3 ): 3607, 3400 (br.), 3065, 3030, 3003, 2928, 2857, 1742, 1705, 1600, 1450, 1376, 1155, 1084, 1002, 972 cm -1 .
86.4 mg (5Z,13E)-(9R,11R,15S)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-16,17,18-,19,20-
pentanor-5,13-prostadiensäuremethylester aus Beispiel 1 werden mit 157.3 mg 3-Amino-
1-propanol versetzt und 24 Stunden bei 80°C unter Argon gerührt. Das Reaktionsgemisch
reinigt man durch Säulenchromatographie an Kieselgel. Mit CH2Cl2 / 0 - 50% Methanol
als Elutionsmittel erhält man 30.5 mg der Titelverbindung als farbloses Öl.
IR (Flüssig-Kap.): 3310 (br.), 3100, 3008, 2927, 2853, 1643, 1630, 1553, 1448, 1348,
1260, 1080, 1072, 1003, 970 cm-1.
86.4 mg (5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11.15-dihydroxy-16.17, 18-, 19.20-pentanor-5.13-prostadienoic acid methyl ester from example 1 are mixed with 157.3 mg of 3-amino-1-propanol and stirred for 24 hours at 80 ° C. under argon. The reaction mixture is purified by column chromatography on silica gel. With CH 2 Cl 2/0 - 50% methanol as eluent is obtained 30.5 mg of the title compound as a colorless oil.
IR (liquid cap.): 3310 (br.), 3100, 3008, 2927, 2853, 1643, 1630, 1553, 1448, 1348, 1260, 1080, 1072, 1003, 970 cm -1 .
Zu einer Lösung aus 92 mg (5Z,13E)-(9R,11R,15S)-9-Chlor-3-oxa-15-cyclohexyl-11,15-
dihydroxy-16,17,18,19,20-pentanor-5,13-prostadiensäure und 105 mg w-Bromacetophe
non in 2.5 ml Acetonitril gibt man 0.052 ml Triethylamin in 1.0 ml Aceton und rührt an
schließend 18 Stunden bei 24°C unter Argon. Dann verdünnt man mit 60 ml Essigester,
wäscht zweimal mit je 10 ml einer Mischung aus gesättigter Natriumchlorid-Lösung und
Wasser (1 : 1), trocknet über Natriumsulfat und engt im Vakuum ein. Das Rohprodukt rei
nigt man durch Säulenchromatographie an Kieselgel. Mit Hexan / 0-80% Essigester als
Elutionsmittel erhält man 82.6 mg der Titelverbindung als farbloses Öl.
IR (CHCl3): 3605, 3410 (br.), 3030, 2998, 2927, 2853, 1763, 1730, 1704, 1600, 1450,
1375, 1245, 1190, 1180, 1127, 1000, 972 cm-1.To a solution of 92 mg (5Z, 13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11.15-dihydroxy-16.17, 18.19.20-pentanor- 5,13-prostadienoic acid and 105 mg w-bromoacetophe non in 2.5 ml acetonitrile are added 0.052 ml triethylamine in 1.0 ml acetone and then stirred for 18 hours at 24 ° C under argon. Then diluted with 60 ml of ethyl acetate, washed twice with 10 ml of a mixture of saturated sodium chloride solution and water (1: 1), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by column chromatography on silica gel. With hexane / 0-80% ethyl acetate as the eluent, 82.6 mg of the title compound are obtained as a colorless oil.
IR (CHCl 3 ): 3605, 3410 (br.), 3030, 2998, 2927, 2853, 1763, 1730, 1704, 1600, 1450, 1375, 1245, 1190, 1180, 1127, 1000, 972 cm -1 .
80 mg (5Z,13E)-(9R,11R,15S)-9-Chlor-3-oxa-15-cyclohexyl-11,15-dihydroxy-
16,17,18,19,20-pentanor-5,13-prostadiensäuremethylester aus Beispiel 6 werden mit 149.7
mg 3-Amino-1-propanol versetzt und 24 Stunden bei 80°C unter Argon gerührt. Das Re
aktionsgemisch reinigt man durch Säulenchromatographie an Kieselgel. Mit CH2Cl2 / 0-
50% Methanol als Elutionsmittel erhält man 49.6 mg der Titelverbindung als farbloses Öl.
IR (Flüssig-Kap.): 3362 (br.), 3023, 2928, 2854, 1657, 1543, 1450, 1335, 1304, 1273,
1102, 1006, 972 cm-1.
80 mg (5Z, 13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11,15-dihydroxy- 16,17,18,19,20-pentanor-5,13- Methyl prostadienate from Example 6 are mixed with 149.7 mg of 3-amino-1-propanol and stirred for 24 hours at 80 ° C. under argon. The reaction mixture is purified by column chromatography on silica gel. With CH 2 Cl 2 / 0- 50% methanol as the eluent, 49.6 mg of the title compound are obtained as a colorless oil.
IR (liquid cap.): 3362 (br.), 3023, 2928, 2854, 1657, 1543, 1450, 1335, 1304, 1273, 1102, 1006, 972 cm -1 .
Die Hautdurchblutung wurde mit der nichtinvasiven Laser-Doppler Methode bestimmt. Die Messungen wurden 4 Stunden nach der lokalen Applikation der Substanzen auf der Bauchhaut von narkotisierten (Urethan) haarlosen Ratten (für diese Untersuchungen wurden weibliche Ratten (Wister; hairless) mit einem Körpergewicht von 200-250 g verwendet) durchgeführt. Als Lösungsmittel wurde Isopropylmyristat in Ethanol verwendet (5/95; v/v).The blood flow to the skin was determined using the non-invasive laser Doppler method. The measurements were taken 4 hours after the local application of the substances on the Abdominal skin from anesthetized (urethane) hairless rats (for these examinations female rats (Wister; hairless) with a body weight of 200-250 g used) performed. When Solvent isopropyl myristate in ethanol was used (5/95; v / v).
Claims (7)
X Sauerstoff oder CH2,
R1 COOR2,
wobei R2 einen gegebenenfalls substituierten Phenacyl-Rest darstellt,
oder CONHR3
mit R3 in der Bedeutung eines gegebenenfalls substituierten C1-C10-Alkyl- Restes,
bedeuten sowie deren Cyclodextrinclathrate.1. 9-chloro-prostaglandin esters and amides of the general formula (I) wherein
X is oxygen or CH 2 ,
R 1 COOR 2 ,
where R 2 represents an optionally substituted phenacyl radical,
or CONHR 3
with R 3 as an optionally substituted C 1 -C 10 alkyl radical,
mean and their cyclodextrin clathrates.
- a) eine Verbindung der Formel II
worin
X die oben angegebene Bedeutung aufweist,
unter Zusatz einer geeigneten Base mit einem gegebenenfalls substituierten Halogenacetophenonderivat der allgemeinen Formel III worin
R4 C1-C4-Alkyl-, Chlor, Brom, oder Iod und
Hal Chlor oder Brom bedeuten,
in einem polaren Lösungsmittel zu Verbindungen der allgemeinen Formel (Ia) umsetzt, oder - b) einen Alkylester der allgemeinen Formel Ib
worin
X die oben angegebene Bedeutung aufweist,
ohne Lösungsmittel mit einem Amin der allgemeinen Formel IVH2N-R3 (IV)zu Verbindungen der allgemeinen Formel Ic umsetzt und die erhaltenen Verbindungen der allgemeinen Formeln Ia oder Ic gegebenenfalls in die Cyclodextrinclathrate überführt.
- a) a compound of formula II wherein
X has the meaning given above,
with the addition of a suitable base with an optionally substituted haloacetophenone derivative of the general formula III wherein
R 4 is C 1 -C 4 alkyl, chlorine, bromine, or iodine and
Hal means chlorine or bromine,
in a polar solvent to give compounds of the general formula (Ia), or - b) an alkyl ester of the general formula Ib wherein
X has the meaning given above,
without solvent with an amine of the general formula IVH 2 NR 3 (IV) to give compounds of the general formula Ic implemented and the compounds of general formulas Ia or Ic optionally converted into the cyclodextrin clathrates.
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4229050A DE4229050A1 (en) | 1992-08-31 | 1992-08-31 | New esters and amides of 9-chloro-prostaglandins - useful, e.g., in treatment of glaucoma and as diuretic agents |
| JP6506751A JPH08500597A (en) | 1992-08-31 | 1993-08-31 | 9-Chloro-prostaglandin-ester and 9-chloro-prostaglandinamide and the use of said 9-chloro-prostaglandin-ester and 9-chloro-prostaglandinamide for the manufacture of a medicament |
| DE59308617T DE59308617D1 (en) | 1992-08-31 | 1993-08-31 | 9-CHLORINE PROSTAGLANDIN ESTERS AND AMIDES AND THEIR USE FOR THE PRODUCTION OF MEDICINAL PRODUCTS |
| AT93918946T ATE166642T1 (en) | 1992-08-31 | 1993-08-31 | 9-CHLORINE-PROSTAGLANDIN ESTERS AND AMIDES AND THEIR USE FOR THE PRODUCTION OF MEDICINAL PRODUCTS |
| ES93918946T ES2118248T3 (en) | 1992-08-31 | 1993-08-31 | 9-CHLORINE-PROSTAGLANDINE ESTERS AND AMIDES AND THEIR USE TO PREPARE MEDICINES. |
| EP93918946A EP0656889B1 (en) | 1992-08-31 | 1993-08-31 | 9-chloroprostaglandin esters and amides and their use in the preparation of drugs |
| PCT/DE1993/000809 WO1994005631A1 (en) | 1992-08-31 | 1993-08-31 | 9-chloroprostaglandin esters and amides and their use in the preparation of drugs |
| DK93918946T DK0656889T3 (en) | 1992-08-31 | 1993-08-31 | 9-chloro-prostaglandin esters and amides and their use in the manufacture of drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4229050A DE4229050A1 (en) | 1992-08-31 | 1992-08-31 | New esters and amides of 9-chloro-prostaglandins - useful, e.g., in treatment of glaucoma and as diuretic agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE4229050A1 true DE4229050A1 (en) | 1994-03-03 |
Family
ID=6466904
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE4229050A Withdrawn DE4229050A1 (en) | 1992-08-31 | 1992-08-31 | New esters and amides of 9-chloro-prostaglandins - useful, e.g., in treatment of glaucoma and as diuretic agents |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE4229050A1 (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5627209A (en) * | 1993-12-15 | 1997-05-06 | Alcon Laboratories, Inc. | Use of certain 9-haloprostaglandins to treat glaucoma and ocular hypertension |
| US5721273A (en) * | 1993-12-15 | 1998-02-24 | Alcon Laboratories, Inc. | Use of certain 9-halo-13,14-dihydroprostaglandins to treat glaucoma and ocular hypertension |
| US5807892A (en) * | 1994-09-30 | 1998-09-15 | Alcon Laboratories, Inc. | Use of certain prostaglandin analogues to treat glaucoma and ocular hypertension |
| US5814660A (en) * | 1995-12-22 | 1998-09-29 | Alcon Laboratories, Inc. | 9-oxa prostaglandin analogs as ocular hypotensives |
| US5866602A (en) * | 1995-12-22 | 1999-02-02 | Alcon Laboratories, Inc. | Keto-substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives |
| US6211226B1 (en) | 1998-12-17 | 2001-04-03 | Alcon Laboratories, Inc. | 11-Aza prostaglandins for the treatment of glaucoma and ocular hypertension |
| US6232344B1 (en) | 1997-12-22 | 2001-05-15 | Alcon Laboratories, Inc. | 13-Oxa prostaglandins for the treatment of glaucoma and ocular hypertension |
| US6417228B1 (en) | 1998-11-02 | 2002-07-09 | Alcon Manufacturing, Ltd.. | 13-Aza prostaglandins for the treatment of glaucoma and ocular hypertension |
| US6649653B1 (en) | 1996-11-12 | 2003-11-18 | Alcon Manufacturing, Ltd. | 15-fluoro prostaglandins as ocular hypotensives |
| US6680339B2 (en) | 1996-11-12 | 2004-01-20 | Alcon Manufacturing, Ltd. | 15-fluoro prostaglandins as ocular hypotensives |
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| SU1026652A3 (en) * | 1979-12-10 | 1983-06-30 | Шеринг Аг (Фирма) | Process for preparing derivatives of 9-chloroprostane or their salts |
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| EP0299914A1 (en) * | 1987-07-17 | 1989-01-18 | Schering Aktiengesellschaft | 9-Halogen (Z) prostaglandin derivatives, process for their production and their use as medicines |
| DE4008925A1 (en) * | 1990-03-16 | 1991-09-19 | Schering Ag | New clathrates of 9-chloro-prostaglandin(s) with beta-cyclodextrin |
| DE4036140A1 (en) * | 1990-11-09 | 1992-05-14 | Schering Ag | 9-HALOGEN-11SS-HYDROXY-PROSTAGLANDIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
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1992
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| SU1026652A3 (en) * | 1979-12-10 | 1983-06-30 | Шеринг Аг (Фирма) | Process for preparing derivatives of 9-chloroprostane or their salts |
| DE3504044A1 (en) * | 1985-02-04 | 1986-08-07 | Schering AG, Berlin und Bergkamen, 1000 Berlin | 9-HALOGEN PROSTAGLANDIN CLATHRATE AND THEIR USE AS A MEDICINAL PRODUCT |
| DE3510978A1 (en) * | 1985-03-22 | 1986-09-25 | Schering AG, Berlin und Bergkamen, 1000 Berlin | NEW 9-HALOGEN PROSTAGLANDINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| EP0299914A1 (en) * | 1987-07-17 | 1989-01-18 | Schering Aktiengesellschaft | 9-Halogen (Z) prostaglandin derivatives, process for their production and their use as medicines |
| DE4008925A1 (en) * | 1990-03-16 | 1991-09-19 | Schering Ag | New clathrates of 9-chloro-prostaglandin(s) with beta-cyclodextrin |
| DE4036140A1 (en) * | 1990-11-09 | 1992-05-14 | Schering Ag | 9-HALOGEN-11SS-HYDROXY-PROSTAGLANDIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5627209A (en) * | 1993-12-15 | 1997-05-06 | Alcon Laboratories, Inc. | Use of certain 9-haloprostaglandins to treat glaucoma and ocular hypertension |
| US5721273A (en) * | 1993-12-15 | 1998-02-24 | Alcon Laboratories, Inc. | Use of certain 9-halo-13,14-dihydroprostaglandins to treat glaucoma and ocular hypertension |
| US6344581B1 (en) | 1993-12-15 | 2002-02-05 | Alcon Manufacturing, Ltd. | Method of prostaglandin synthesis |
| US6531614B2 (en) | 1993-12-15 | 2003-03-11 | Alcon Manufacturing, Ltd. | Method of prostaglandin synthesis |
| US5807892A (en) * | 1994-09-30 | 1998-09-15 | Alcon Laboratories, Inc. | Use of certain prostaglandin analogues to treat glaucoma and ocular hypertension |
| US5814660A (en) * | 1995-12-22 | 1998-09-29 | Alcon Laboratories, Inc. | 9-oxa prostaglandin analogs as ocular hypotensives |
| US5866602A (en) * | 1995-12-22 | 1999-02-02 | Alcon Laboratories, Inc. | Keto-substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives |
| US6649653B1 (en) | 1996-11-12 | 2003-11-18 | Alcon Manufacturing, Ltd. | 15-fluoro prostaglandins as ocular hypotensives |
| US6680339B2 (en) | 1996-11-12 | 2004-01-20 | Alcon Manufacturing, Ltd. | 15-fluoro prostaglandins as ocular hypotensives |
| US6232344B1 (en) | 1997-12-22 | 2001-05-15 | Alcon Laboratories, Inc. | 13-Oxa prostaglandins for the treatment of glaucoma and ocular hypertension |
| US6417228B1 (en) | 1998-11-02 | 2002-07-09 | Alcon Manufacturing, Ltd.. | 13-Aza prostaglandins for the treatment of glaucoma and ocular hypertension |
| US6211226B1 (en) | 1998-12-17 | 2001-04-03 | Alcon Laboratories, Inc. | 11-Aza prostaglandins for the treatment of glaucoma and ocular hypertension |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| OM8 | Search report available as to paragraph 43 lit. 1 sentence 1 patent law | ||
| 8127 | New person/name/address of the applicant |
Owner name: SCHERING AG, 13353 BERLIN, DE |
|
| 8141 | Disposal/no request for examination |